Background: Despite major advances in the management of ventilator-associated pneumonia, its pathogenesis is not clearly known. Recently, the role of gastric colonization has been proposed. We compared the prevalence of H. pylori by serology in patients with VAP and in control subjects to determine the role of H. pylori and gastric colonization in the pathogenesis of VAP.



Methods:118 intubated and mechanically ventilated patients were included and divided into two groups; 59 subjects with VAP and 59 control patients. Results of the serologic tests, demographic characteristics and time of blood sampling were registered.



Results: Mean age in seropositive patients was significantly higher. 71.2% in the VAP group and 61.01% in controls were IgG seropositive (P=0.24). IgM seropositivity was 23.73% versus 8.47% in VAPs and controls, respectively (P=0.024). By increasing the time of intubation, more patients became seropositive for IgM (Pearson’s correlation coefficient=0.4, P=0.002).











Conclusion:  IgM seropositivity and serum level were significantly higher in VAP patients. Also by increasing the duration of intubation and time of sampling, serum levels and seropositivity for IgM increased significantly

Alireza Dadashi

Ebadallah Shiri Malekabad

Hossein Ghaderi

Nima Hosseinzadeh

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J Med Bacteriol. Vol. 8, No. 1, 2 (2019): pp.21-26 jmb.tums.ac.ir   *Corresponding Author: Ebadallah Shiri Malekabad, Infectious Disease Department, AJA University of Medical Sciences, Tehran, Iran. Tel: +98- 021-43822457, E-mail: ebad.shiri1986@gmail.com   High Seroprevalence of Anti-H. pylori Antibodies in Patients with  Ventilator Associated Pneumonia Alireza Dadashi 1, Nima Hosseinzadeh 2, Ebadallah Shiri Malekabad 3*,  Hossein Ghaderi 4 1 Infectious Disease Department, AJA University of Medical Sciences, Tehran, Iran. 2 Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran. 3 Department of Social Medicine, Army University of Medical Sciences (AJA), Tehran, Iran. 4 Department of Bacteriology, Shiraz University, Shiraz, Iran.                                               Please cite this paper as: Dadashi A, Hosseinzadeh N, Shiri Malekabad E, Ghaderi H. High Seroprevalence of Anti-H. pylori Antibodies in Patients with Ventilator Associated Pneumonia. J Med Bacteriol. 2019; 8 (1, 2): pp.21-26.       ARTICLE  INFO  ABSTRACT Article type: Original Article Background:      Despite major advances in the management of ventilator-associated pneumonia, its pathogenesis is not clearly known. Recently, the role of gastric colonization has been proposed. We compared the prevalence of H. pylori by serology in patients with VAP and in control subjects to determine the role of H. pylori and gastric colonization in the pathogenesis of VAP. Methods:    118 intubated and mechanically ventilated patients were included and divided into two groups; 59 subjects with VAP and 59 control patients. Results of the serologic tests, demographic characteristics and time of blood sampling were registered. Results:      Mean age in seropositive patients was significantly higher. 71.2% in the VAP group and 61.01% in controls were IgG seropositive (P=0.24). IgM seropositivity was 23.73% versus 8.47% in VAPs and controls, respectively (P=0.024). By increasing the time of intubation, more patients became seropositive for IgM (Pearson’s correlation coefficient=0.4, P=0.002). Conclusion:      IgM seropositivity and serum level were significantly higher in VAP patients. Also by increasing the duration of intubation and time of sampling, serum levels and seropositivity for IgM increased significantly. Article history: Received: 16 Nov 2018 Revised:  17 Nov 2018 Accepted:   29  Nov  2018 Published:  20  Feb   2019 Keywords: Gastric colonization, Helicobacter pylori, Pathogenesis; Serology, Ventilator-associated pneumonia. Journal of Medical Bacteriology       High Seroprevalence of Anti-H. pylori …                                                                                                                                 Dadashi A, et al.  J Med Bacteriol.                   Vol. 8, No. 1, 2 (2019): pp.21-26                jmb.tums.ac.ir 22      Introduction  Ventilator-associated pneumonia (VAP) is defined as pneumonia that occurs 48 hours after the initiation of endotracheal intubation and is clinically suspected when leukocytosis, fever, purulent tracheal secretions and development of new or progressive infiltrate on chest radiograph are seen (1). It is the most common infection in intensive-care-unit (ICU), affecting 6 to 52% of patients (2). Recently, the role of gastric colonization in the pathogenesis of the VAP has been proposed (3). Some studies have shown that stomach is colonized by enteric Gram-negative bacilli (GNB) and increasing the gastric PH is the main predisposing factor (4, 5).    Helicobacter pylori (H. pylori) is a Gram-negative bacillus which colonizes the stomach. The prevalence of H. pylori is up to 80% among adults in developing countries (6). This organism produces the urease enzyme that catalyzes the  hydrolysis of urea into ammonia and CO2 which leads to gastric pH alteration (6). Few studies have demonstrated that H. pylori can gain access to the bronchial tree and may cause pneumonia due to GNB (7). Also, recent studies suggest that there might be an association between H. pylori infection and respiratory diseases (8, 9). Several pathogenic mechanisms have been proposed including activation of inflammatory mediators by H. pylori infection, inhalation of H. pylori or its exotoxins into the respiratory tract and genetic predisposition (10, 11).    Despite major advances in the management of VAP patients, the mortality rate is relatively high ranging from 20% to 76% (12, 13). More knowledge about the pathogenesis of VAP, could improve prevention and treatment options. In this study, we aimed to evaluate the prevalence of H. pylori by serology in patients with VAP and compare it with control subjects to determine the role of H. pylori and gastric colonization in the pathogenesis of VAP.   Materials and Methods Study Design     This case-control, a retrospective study was conducted in Imam Reza Hospital (Tehran, Iran), a referral care university teaching hospital, from August 2014 to November 2015.  Patient selection     118 patients who were intubated and mechanically ventilated in ICU at least 48 hours were enrolled in the study. All patients aged 18 to 75 years old.     The case group has consisted of 59 patients with VAP. The diagnosis was made based on the presence of at least 3 from 4 major clinical criteria including leukocytosis, fever, purulent tracheal secretions and development of new or progressive infiltrate on chest radiograph.     There were also 59 controls who were matched with cases in gender and age to decrease the effect of confounding factors.  Sampling     All patients (cases and controls) underwent blood sampling for assessment of anti-H. pylori IgM and IgG serologic tests with enzyme-linked immunosorbent assay (ELISA) (Monobind Inc, Lake Forest, California). When the serum level of IgM antibodies against H. pylori was ≥20, between 10 and 20 and ≤10 U/ml, the result was considered as positive, equivocal and negative, respectively. Also, for IgG antibodies these serum levels were ≥12, between 8 and 12 and ≤8 respectively. Equivocal results were excluded from further analysis. Sample analysis was done by technicians who were unaware of the patient’s condition. Results of the serologic tests, demographic characteristics of the patients and time of blood sampling (days after intubation) were registered in Data entry form.         High Seroprevalence of Anti-H. pylori …                                                                                                                                 Dadashi A, et al.  J Med Bacteriol.                   Vol. 8, No. 1, 2 (2019): pp.21-26                jmb.tums.ac.ir 23  Ethical consideration     Informed consent was obtained from all subjects prior to the study. Patients’ information remained confidential. All aspects of this study were approved by the Institutional Review Board of the AJA University of Medical Sciences.  Statistical analysis     Analysis was performed using the SPSS ver.18 (SPSS Inc., Chicago, USA). For analysis the difference between groups, χ2-test and Independent Samples T-Test were used to compare proportions and continuous variables, respectively. A P-value<0.05 was considered statistically significant.  Result     Demographic characteristics of the participants are shown in table 1. There was no significant difference in age or gender distribution and intubated days between the groups (p>0.05).    From all 118 participants, 66.1% (78 patients) and 16.1% (19 patients) were seropositive for IgG and IgM, respectively. Mean age in seropositive patients was significantly higher than others (53.59 versus 38.45 for IgG+ and IgG- subjects, respectively, P<0.001 and 60.74 versus 46.1 for IgM+ and IgM- subjects, respectively, P<0.001). 71.2% in the VAP group and 61.01% in controls were IgG seropositive which the difference was not significant (P=0.24). Also, the serum level of IgG was not significantly different between the groups (P=0.16). More information is shown in table 2.    IgM seropositivity was 23.73% versus 8.47% in VAPs and controls, respectively which was significant (P=0.024). Also, there was a significant difference in serum level of IgM between groups (P=0.041).    In all patients, intubation days were higher in seropositive patients for both IgG and IgM but the difference was only significant in IgM positive patients (6 ± 2.42 for IgG+ vs. 5.3 ± 1.6 for IgG-, P=0.1 and 6.89 ± 2.26 for IgM+ vs. 5.55 ± 2.13 for IgM-, P=0.014). Also, intubation days for IgM positive patients were significantly higher only in the VAP group (7.07 ± 2.34 vs. 5.42 ± 2.08 for IgM+ and IgM- patients, respectively, P=0.014).    For understanding the relationship between IgM results and intubation days, a bivariate correlation was used. Analysis of the results in VAP group showed that there is the direct and significant relationship between IgM results and intubation days (Pearson’s correlation coefficient=0.4, P=0.002), in other words by increasing the time of intubation, more patients became seropositive for IgM.  Discussion     There is no consensus about the role of gastric colonization in the pathogenesis of VAP. Also there are numerable studies about H. pylori as the most common pathogen which colonizes the stomach and its association with VAP. In the recent study, the prevalence of seropositive patients for H. pylori was evaluated and compared between two groups of patients including cases and controls to determine the role of H. pylori in the pathogenesis of VAP.    The mean age of IgM and IgG-seropositive patients was significantly higher. In developed countries H. pylori infection is more prevalent in childhood and adolescent, so many adults are seropositive for IgG and the risk of infection is more in older ages. These findings are consistent with several studies which found older patients have a higher IgG level (14-17).    Although IgG and IgM seropositivity and serum level were higher in VAP patients only IgM results were significant. Also by increasing the duration of intubation and time of sampling, serum levels and seropositivity for IgM increased significantly. These findings demonstrate that there are higher rates of acute and chronic H. pylori infection in VAP patients. Higher IgG levels could be explained by older ages and probably more comorbidity in VAP patients, but there is no explanation for higher IgM levels        High Seroprevalence of Anti-H. pylori …                                                                                                                                 Dadashi A, et al.  J Med Bacteriol.                   Vol. 8, No. 1, 2 (2019): pp.21-26                jmb.tums.ac.ir 24                                 because it increases in acute infection. It is unlikely to consider IgM rise due to acute primary H. pylori infection because of patient’s age and condition. They have hospitalized in ICU and H. pylori transmission is not a possible route of infection. To explain these findings there is 3 possible hypothesis: 1) Several studies have demonstrated the association between increasing gastric pH and GNB colonization (4, 5). In intubated patients, rates of gastroesophageal reflux are higher (18, 19); so it is possible that in VAP patients, H. pylori colonizes the stomach and cause GNB colonization by gastric PH alteration. Then, gastroesophageal reflux and oropharyngeal colonization of GNB occurs and aspiration of colonized bacteria might cause VAP in these patients. This stomach-pharynx-lower respiratory tract infection route has been shown in many studies (4, 7, 20). 2) Gastroesophageal reflux and aspiration of H. pylori could help it reach to tracheobronchial tree. It made the environment susceptible for GNB colonization and development of VAP. Also it is possible that H. pylori cause VAP primarily by Inflammation of the respiratory membrane by its proteins. Mitz et al. (7) study supports this hypothesis but, more studies with a precise microbiologic assessment to determine the exact origin of the pathogens are needed. 3) Another possible hypothesis is activation of systemic inflammatory mediators by H. pylori proteins or inhalation of H. pylori or its exotoxins into the respiratory tract and development of VAP. Studies which have been assessed the association between H. pylori infection and respiratory diseases will support this idea (8-11). Future studies are needed to evaluate systemic or respiratory inflammatory factors involved in the pathogenesis of VAP and their association with H. pylori infection.  Conclusion     IgM seropositivity and serum level were significantly higher in VAP patients. Also by increasing the duration of intubation and time of sampling, serum levels and seropositivity for IgM increased significantly. H. pylori infection, subsequent GNB colonization and aspiration to a tracheobronchial tree or systemic inflammation are possible causes. Further studies with larger Table 1.         Demographic characteristics of the participants. Parameter VAP No VAP P-value Age 50.34 ± 14.72a 46.58 ± 15.42 0.18 Gender 37 males 22 females 41 males 18 females 0.43 Days intubated 5.81 ± 2.24 (2-12)b 5.71 ± 2.17 (2-13) 0.8 a: Mean ± Standard Deviation b: range (minimum-maximum) Table 2.          Detailed information about serology results in cases and controls. parameter VAP No VAP P-value IgG seropositivity 42 (71.2%) 34 (61.01%) 0.24 serum level (u/ml) 52.31 41.1 0.16 IgM seropositivity 14 (23.73%) 5 (8.47%) 0.024 serum level (u/ml) 22.17 14.31 0.041       High Seroprevalence of Anti-H. pylori …                                                                                                                                 Dadashi A, et al.  J Med Bacteriol.                   Vol. 8, No. 1, 2 (2019): pp.21-26                jmb.tums.ac.ir 25  sample sizes, detailed and precise laboratory and microbiologic assessment are needed to evaluate the possible role of H. pylori in the pathogenesis of VAP.  Conflict of interest     The authors declare that they have no conflict of interest.  References  1. Koenig SM, Truwit JD. Ventilator-associated pneumonia: diagnosis, treatment, and prevention. Clin Microbiol Rev 2006; 19(4):637-57. 2. Cosme AE, Jesus HT, Luis Francisco SA, et al. High Seroprevalence of Helicobacter pylori Infection in  Inmates: a case control study in a northern mexican city. Gastroenterology Res 2013; 6(6):227-32. 3. Joseph NM, Sistla S, Dutta TK, et al. Ventilator-associated pneumonia: a review. Eur J Intern Med 2010; 21(5):360-8. 4. Li HY, He LX, Hu BJ, et al. The impact of gastric colonization on the pathogenesis of ventilator-associated pneumonia. Zhonghua Nei Ke Za Zhi 2004; 43(2):112-6. 5. Torres A, El-Ebiary M, Soler N, et al. Stomach as a source of colonization of the respiratory tract during mechanical ventilation: association with ventilator-associated pneumonia. Eur Respir J 1996; 9(8):1729-35. 6. Dan Longo AF, Kasper D, Hauser S. Helicobacter pylori Infections. In: John C. Atherton MJB, editor. Harrison's Principles of Internal Medicine; 18th ed: McGraw-Hill; 2011, p:1261-5. 7. Mitz HS, Farber SS. Demonstration of Helicobacter pylori in tracheal secretions. J Am Osteopath Assoc 1993; 93(1):87-91. 8. Roussos A, Philippou N, Mantzaris GJ, et al. Respiratory diseases and Helicobacter pylori infection. Respir Med 2006; 73(5):708-14. 9. Tsang KW, Lam SK, Lam WK, et al. High seroprevalence of Helicobacter pylori in active bronchiectasis. Am J Respir Crit Care Med 1998; 158(4):1047-51. 10. Roussos A, Philippou N, Gourgoulianis KI. Helicobacter pylori infection and respiratory diseases: a review. World J Gastroenterol 2003; 9(1):5-8. 11. Roussos A, Philippou N, Krietsepi V, et al. Helicobacter pylori seroprevalence in patients with chronic obstructive pulmonary disease. Respir Med 2005; 99(3): 279-84. 12. Alp E, Voss A. Ventilator associated pneumonia and infection control. Ann Clin Microbiol Antimicrob 2006; 5:7. 13. Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med 2002 1; 165(7):867-903. 14. Dutra Souto FJ, Jesus Fernandes Fontes C, Aguiar Rocha G, et al. Prevalence of Helicobacter pylori infection in a rural area of the state of Mato Grosso, Brazil. Memórias do Instituto Oswaldo Cruz 1998; 93:171-4. 15. Kim N. Epidemiology and transmission route of Helicobacter pylori infection. Korean J Gastroenterol 2005; 46(3):153-8. 16. Lim SH, Kwon JW, Kim N, et al. Prevalence and risk factors of Helicobacter pylori infection in Korea: nationwide multicenter study over 13 years. BMC Gastroenterol 2013; 13:104. 17. Miranda ACP, Machado RS, Silva EMKD, et al. Seroprevalence of Helicobacter pylori infection among children of low socioeconomic level in São Paulo. Sao Paulo Medical Journal 2010; 128:187-91. 18. Abdel-Gawad TA, El-Hodhod MA, Ibrahim HM, et al. Gastroesophageal reflux in mechanically ventilated pediatric patients and its relation to ventilator-associated pneumonia. Crit Care 2009; 13(5):164. 19. Nind G, Chen WH, Protheroe R, et al. Mechanisms of gastroesophageal reflux in critically ill mechanically ventilated patients. Gastroenterology 2005; 128(3):600-6. 20. Estes RJ, Meduri GU. The pathogenesis of       High Seroprevalence of Anti-H. pylori …                                                                                                                                 Dadashi A, et al.  J Med Bacteriol.                   Vol. 8, No. 1, 2 (2019): pp.21-26                jmb.tums.ac.ir 26  ventilator-associated pneumonia: I. Mechanisms of bacterial transcolonization and airway inoculation. 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High Seroprevalence of Anti-H. pylori Antibodies in Patients with  Ventilator Associated Pneumonia

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High Seroprevalence of Anti-H. pylori Antibodies in Patients with Ventilator Associated Pneumonia

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